The effects of cyclosporin A (CSA) on IgE receptor-mediated exocytosis from rat basophilic leukemia (RBL) cells was examined. Both IgE receptor-mediated and Ca2+ ionophore-induced degranulation were inhibited 50% in the presence of 0.2 (mu)g/ml CSA. This is the concentration of CSA achieved in the plasma of patients undergoing immunosuppressive therapy with CSA. Whereas inhibition of lymphokine expression requires lengthy (hours) preincubation with the drug, maximum inhibition of degranulation from RBL cells occurs after a 5 min preincubation with CSA. CSA does not have to be present in the buffer at the time of stimulation. If RBL cells are incubated with CSA for 15 min, washed, and triggered in the absence of CSA, release is still inhibited. The inhibition of degranulation is not limited to RBL cells. IgE receptor-mediated histamine release from human basophils was inhibited by the same range of CSA concentrations that inhibits release from RBL cells. Concentrations of CSA that results in maximum inhibition of secretion have no effect on "early" events in signal transduction such as receptor-mediated PI hydrolysis, Ca2+ influx, or the rise in the concentration of Ca2+ in the cytosol. Moreover, actin polymerization and cell viability are not affected. In addition, not all secretory cells are inhibited by CSA. Degranulation of rat pancreatic acinar cells in response to bombesin is not inhibited by concentrations of CSA that causes maximum inhibition of release from RBL cells and human basophils. These results demonstrate that the early events in signal transduction are not affected, and suggest that the intracellular target for CSA participates in a later stage of exocytosis. Furthermore, the data suggest that CSA suppresses other cells than T-lymphocytes and predict that patients on CSA therapy may have altered response to allergens.